Groves, A.K. etal. Repair of demyelinated lesions by transplantation of purified O-2A progenitor cells. Nature 362, 453- 455

Department of Veterinary Medicine, University of Cambridge, Cambridge, England, United Kingdom
Nature (Impact Factor: 42.35). 05/1993; 362(6419):453-5. DOI: 10.1038/362453a0
Source: PubMed

ABSTRACT The transplantation of well defined populations of precursor cells offers a means of repairing damaged tissue and of delivering therapeutic compounds to sites of injury or degeneration. For example, a functional immune system can be reconstituted by transplantation of purified haematopoietic stem cells, and transplanted skeletal myoblasts and keratinocytes can participate in the formation of normal tissue in host animals. Cell transplantation in the central nervous system (CNS) has been proposed as a means of correcting neuronal dysfunction in diseases associated with neuronal loss; it might also rectify glial cell dysfunction, with transplanted oligodendrocyte precursor cells eventually allowing repair of demyelinating damage in the CNS. Here we use co-operating growth factors to expand purified populations of oligodendrocyte type-2 astrocyte (O-2A) progenitor cells for several weeks in vitro. When injected into demyelinating lesions in spinal cords of adult rats, created in such a way as to preclude host-mediated remyelination, these expanded populations are capable of producing extensive remyelination. In addition, transplantation of O-2A progenitor cells genetically modified to express the bacterial beta-galactosidase gene gives rise to beta-galactosidase-positive oligodendrocytes which remyelinate demyelinated axons within the lesion. These results offer a viable strategy for the manipulation of neural precursor cells which is compatible with attempts to repair damaged CNS tissue by precursor transplantation.

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    • "Glial cell death via apoptosis, particularly loss of myelinating OLGs, may result in consequent axonal demyelination (Jensen et al. 1999; Tamura et al. 2005; Warden et al. 2001). In support this hypothesis, remyelination of the spinal cord axons via cell transplantation (Akiyama et al. 2002; Groves et al. 1993; Keirstead et al. 2005) or transplants combined with cAMP elevation or neurotrophic factors (Cao et al. 2005; Pearse et al. 2004) have been shown to improve functional recovery in SCI rodents significantly. In addition, RhoA might negatively regulate myelin formation in the CNS because RhoA activation by Lingo1, a protein present in OLGs, appears to suppress myelination of CNS axons (Mi et al. 2005; Mi et al. 2009). "
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    ABSTRACT: Nonsteroidal anti-inflammatory drugs (NSAIDs) are extensively used to relieve pain and inflammation in humans via cyclooxygenase inhibition. Our recent research suggests that certain NSAIDs including ibuprofen suppress intracellular RhoA signal and improve significant axonal growth and functional recovery following axonal injury in the CNS. Several NSAIDs have been shown to reduce generation of amyloid-beta42 peptide via inactivation of RhoA signal, supporting potent RhoA-repressing function of selected NSAIDs. In this report, we demonstrate that RhoA-inhibiting NSAIDs ibuprofen and indomethacin dramatically reduce cell death of oligodendrocytes in cultures or along the white matter tracts in rats with a spinal cord injury. More importantly, we demonstrate that treatments with the RhoA-inhibiting NSAIDs significantly increase axonal myelination along the white matter tracts following a traumatic contusion spinal cord injury. In contrast, non-RhoA-inhibiting NSAID naproxen does not have such an effect. Thus, our results suggest that RhoA inactivation with certain NSAIDs benefits recovery of injured CNS axons not only by promoting axonal elongation, but by enhancing glial survival and axonal myelination along the disrupted axonal tracts. This study, together with previous reports, supports that RhoA signal is an important therapeutic target for promoting recovery of injured CNS and that RhoA-inhibiting NSAIDs provide great therapeutic potential for CNS axonal injuries in adult mammals.
    Experimental Neurology 07/2011; 231(2):247-60. DOI:10.1016/j.expneurol.2011.06.018 · 4.62 Impact Factor
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    • "Still, one must be cautious in interpretation of these results until a functional assessment of the transplanted cells is performed. Nevertheless, several other studies demonstrate that the ability of OPCs to engraft and myelinate decreases over time in culture (Feltri et al. 1992; Groves et al. 1993; Trotter et al. 1993). Culturing oligodendrocyte-lineage cells may make them less likely to myelinate when transplanted, as they lose their proliferative ability and differentiate in vitro (Richter and Roskams 2008). "
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    ABSTRACT: Oligodendrocytes are the primary source of myelin in the adult central nervous system (CNS), and their dysfunction or loss underlies several diseases of both children and adults. Dysmyelinating and demyelinating diseases are thus attractive targets for cell-based strategies since replacement of a single presumably homogeneous cell type has the potential to restore functional levels of myelin. To understand the obstacles that cell-replacement therapy might face, we review oligodendrocyte biology and emphasize aspects of oligodendrocyte development that will need to be recapitulated by exogenously transplanted cells, including migration from the site of transplantation, axon recognition, terminal differentiation, axon wrapping, and myelin production and maintenance. We summarize studies in which different types of myelin-forming cells have been transplanted into the CNS and highlight the continuing challenges regarding the use of cell-based therapies for human white matter disorders.
    Archivum Immunologiae et Therapiae Experimentalis 04/2011; 59(3):179-93. DOI:10.1007/s00005-011-0120-7 · 2.82 Impact Factor
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    • "These results are consistent with previous studies. Bi-potential OPCs from neonatal optical nerve or brain differentiate along OL lineages without astrocyte commitment after transplantation into the adult demyelinated (Groves et al., 1993) or contused (Lee et al., 2005) spinal cord. Since astrocyte differentiation from grafted NSCs enhances the plasticity of pain fibers and promotes allodynia after SCI (Hofstetter et al., 2005), lack of astrocyte differentiation and concomitant allodynia plus its greatest potential for OL differentiation may make adult OPCs an ideal candidate for cell grafts to OL replacement and remyelination after SCI. "
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    ABSTRACT: Demyelination contributes to the dysfunction after traumatic spinal cord injury (SCI). We explored whether the combination of neurotrophic factors and transplantation of adult rat spinal cord oligodendrocyte precursor cells (OPCs) could enhance remyelination and functional recovery after SCI. Ciliary neurotrophic factor (CNTF) was the most effective neurotrophic factor to promote oligodendrocyte (OL) differentiation and survival of OPCs in vitro. OPCs were infected with retroviruses expressing enhanced green fluorescent protein (EGFP) or CNTF and transplanted into the contused adult thoracic spinal cord 9 d after injury. Seven weeks after transplantation, the grafted OPCs survived and integrated into the injured spinal cord. The survival of grafted CNTF-OPCs increased fourfold compared with EGFP-OPCs. The grafted OPCs differentiated into adenomatus polyposis coli (APC(+)) OLs, and CNTF significantly increased the percentage of APC(+) OLs from grafted OPCs. Immunofluorescent and immunoelectron microscopic analyses showed that the grafted OPCs formed central myelin sheaths around the axons in the injured spinal cord. The number of OL-remyelinated axons in ventrolateral funiculus (VLF) or lateral funiculus (LF) at the injured epicenter was significantly increased in animals that received CNTF-OPC grafts compared with all other groups. Importantly, 75% of rats receiving CNTF-OPC grafts recovered transcranial magnetic motor-evoked potential and magnetic interenlargement reflex responses, indicating that conduction through the demyelinated axons in VLF or LF, respectively, was partially restored. More importantly, recovery of hindlimb locomotor function was significantly enhanced in animals receiving grafts of CNTF-OPCs. Thus, combined treatment with OPC grafts expressing CNTF can enhance remyelination and facilitate functional recovery after traumatic SCI.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 02/2010; 30(8):2989-3001. DOI:10.1523/JNEUROSCI.3174-09.2010 · 6.75 Impact Factor
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